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Neurocardiogenic Syncope Coexisting with Postural
Orthostatic Tachycardia Syndrome in Patients Suffering
from Orthostatic Intolerance: A Combined form
of Autonomic Dysfunction
KHALIL KANJWAL, M.D.,* MUJEEB SHEIKH, M.D.,† BEVERLY KARABIN, PH.D.,*
YOUSUF KANJWAL, M.D.,* and BLAIR P. GRUBB, M.D.*
From the *Section of Electrophysiology, Division of Cardiology, Department of Medicine, The University of Toledo
Medical Center, Toledo, Ohio; and †Division of Internal Medicine, Department of Medicine, The University of
Toledo Medical Center, Toledo, Ohio
Introduction: There is anecdotal evidence that one or more forms of orthostatic intolerance (OI)
subgroups may coexist in the same patients. However, there is a paucity of published data on the clinical
features and management of patients who suffer from coexisting features of postural tachycardia syndrome
(POTS) and neurocardiogenic syncope (NCS). We herein present our experience of 18 patients who we
found displayed evidence of coexisting NCS and POTS.
Methods: We reviewed charts of 300 POTS patients seen at the University of Toledo Syncope and
Autonomic Disorders Center from 2003 to 2010 and found 18 patients eligible for inclusion in this study.
Patients were included in this study if they reported clinical symptoms consistent with both POTS and NCS
and then demonstrated a typical POTS pattern (a rise in heart rate without change in blood pressure [BP])
on head up tilt table (HUTT) within the first 10 minutes of upright posture followed by a neurocardiogenic
pattern (a sudden fall in heart rate and/or fall in blood pressure) reproducing symptoms that were similar
to the patients spontaneous episodes.
Results: We found 18 patients, mean age (30 ± 12), with 15 (84%) women and three (16%) men, who
met the inclusion criterion for this study. Each of these 18 patients demonstrated a typical POTS pattern
within the first 10 minutes on initial physical exam and on a HUTT. Continued tilting beyond 10 minutes
resulted in a sudden decline in heart rate (which in some patients manifested as an asystole that lasted
anywhere between 10 and 32 seconds [mean of 18 seconds]) and/or a fall in BP in each of these patients
demonstrating a pattern consistent with neurocardiogenic subtype of OI. The mean time to the NCS pattern
of a fall in BP and heart was 15 minutes with a range of 13–20 minutes. This group of patients was highly
symptomatic and reported frequent clinical symptoms that were suggestive of OI. Recurrent presyncope,
syncope, orthostatic palpitations, exercise intolerance, and fatigue were the principal symptoms reported.
Conclusion: NCS may coexist with POTS in a subgroup of patients suffering from OI. (PACE 2010;
1–6)
orthostatic intolerance, postural tachycardia syndrome, neurocardiogenic syncope
Introduction
Orthostatic intolerance (OI) syndromes refer to a heterogeneous group of disorders of
hemodynamic regulation that are characterized
by excessive pooling of blood in the dependent
areas of the body during upright posture, thereby
resulting in insufficient cerebral perfusion during
upright posture causing a variety of symptoms
Address for reprints: Blair P. Grubb M.D., F.A.C.C., Division
of Cardiology, Department of Medicine, The University of
Toledo Medical Center, Mail Stop 1118, 3000 Arlington
avenue, Toledo, OH 43614. Fax: 419-383-3041; e-mail:
blair.grubb@utoledo.edu
Received September 12, 2010; revised October 13, 2010;
accepted October 31, 2010.
doi: 10.1111/j.1540-8159.2010.02994.x
that are relieved by recumbency. Symptoms
may include syncope, near syncope, fatigue,
palpitations, exercise intolerance, lightheadedness, diminished concentration, and headache.1–4
Based on clinical presentation and head up tilt
table response (HUTT), OI can be broadly divided
into subgroups that include neurocardiogenic
syncope (NCS), postural tachycardia syndrome
(POTS), and dysautonomic (autonomic failure)
syndromes.
There is anecdotal evidence that one or more
forms of these subgroups may coexist in the same
patients. However, there is paucity of published
data on the clinical features and management of
patients who suffer from coexisting features of
POTS and NCS. We herein present our experience
of 18 patients who we found displayed evidence
of coexisting NCS and POTS.
C 2010 Wiley Periodicals, Inc.
C 2010, The Authors. Journal compilation PACE
2010
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KANJWAL, ET AL.
Criterion for Diagnosis of Combined OI
Methods
This was a retrospective study approved
by our Institutional Review Board (IRB) at the
University of Toledo. We reviewed charts of 300
POTS patients seen at our autonomic center at the
University of Toledo from 2003 to 2010 and found
18 patients eligible for inclusion in this study.
Patients where included in this study if they
reported clinical symptoms consistent with both
POTS and NCS and then demonstrated a typical
POTS pattern (a rise in heart rate without change
in blood pressure) on assuming upright posture
or HUTT within the first 10 minutes followed by
a neurocardiogenic pattern on continued HUTT
(a sudden fall in heart rate and/or fall in blood
pressure) reproducing symptoms that were similar
to the patients spontaneous episodes.
Criterion for Diagnosis of OI
As mentioned earlier, OI consists of a
heterogeneous group of disorders of hemodynamic
regulation characterized by excessive pooling
of blood in the dependent areas of the body
during upright posture resulting in insufficient
cerebral perfusion causing symptoms during
upright posture relieved by recumbency.
Treatment Protocol
The treatment protocols employed were based
on our previous experiences with orthostatic
disorders and are described in detail elsewhere.1–8
Briefly, a sequence of therapies was employed
that included physical counter maneuvers and
aerobic and resistance training as well as increased dietary fluids and sodium. If these were
ineffective, pharmacotherapy was initiated in a
sequence generally consisting of β-blockers, central sympatholytics, fludrocortisone, midodrine,
and selective serotonin reuptake inhibitors, either
alone or in combination.
If patients failed to respond to these medications, second- and third-line medications such
as octreotide, erythropoietin, and pyridostigmine
were employed.
As this was a retrospective chart review, a
formal questionnaire to assess the response to
treatment or assessment of response to treatment
by HUTT testing was not employed. The information about the subjective symptoms and sense
of well being from each patient was collected from
the patient charts, physician communications, and
direct patient inquiry. A treatment was considered
successful if the patient reported that it provided
symptomatic relief.
POTS
POTS was defined as ongoing symptoms of OI
(of greater than 6 months duration) accompanied
by a heart rate increase of at least 30 beats/min
(or a rate that exceeds 120 beats/min) observed
during the first 10 minutes of upright posture
or HUTT occurring in the absence of other
chronic debilitating disorders.1,2 Symptoms may
include fatigue, orthostatic palpitations, exercise
intolerance, lightheadedness, diminished concentration, headache, near syncope, and syncope. In
a retrospective chart review, we collected data,
including demographic information, presenting
symptoms, laboratory data, tilt-table response, and
treatment outcomes.
Neurocardiogenic syncope
NCS was defined as episodic syncope (transient loss of consciousness) with spontaneous
recovery. Criterion for diagnosis of NCS included
a HUTT response consistent with NCS (a sudden
decrease in heart rate and/or decrease in blood
pressure) that reproduced a patient’s spontaneous
symptoms of recurrent transient loss of consciousness with spontaneous recovery.
Statistics
This is an observational study. The statistical
analysis was done by using SPSS 17 version
(SPSS Inc., Chicago, IL, USA). Continuous data
are presented as mean ± standard deviation
and categorical data as percentages. A t-test was
used for comparisons of means, and a statistical
significance was reached at a P value of <0.05.
Protocol for HUTT
The protocol used for tilt table testing
has been described elsewhere,1–8 but basically
consisted of a 70-degree baseline upright tilt for a
period of 30 minutes, during which time heart rate
and blood pressure were monitored continually. If
no symptoms occurred, the patient was lowered to
the supine position and an intravenous infusion
of isoproterenol started with a dose sufficient to
raise the heart rate to 20%–25% above the resting
value. Upright tilt was then repeated for a period
of 15 minutes.
2
Results
A total of 300 charts of patients followed at
the University of Toledo Syncope and Autonomic
Disorders center were screened. These patients
had been seen over a period of 7 years. We found
18 patients, mean age (30 ± 12), with 15 (84%)
women and three (16%) men, who met the inclusion criterion for this study. Table I summarizes
2010
PACE
COEXISTING POTS AND NCS
Table I.
Table II.
Baseline Clinical Characteristics of the Study Patients
(N = 18)
Hemodynamic Parameters as Assessed in an Outpatient
Office. Most of These Patients Demonstrated This
Pattern of Increase in Heart Rate Without Significant
Change in Blood Pressure (POTS Pattern) within 5
Minutes of Standing
Age (years)
Sex (females)
30 ± 12
15 (84%)
Symptoms of orthostatic intolerance
Orthostatic palpitations
Dizziness
Inability to concentrate
Syncope
Presyncope
Fatigue
Chest pain
17 (95%)
16 (89%)
16 (89%)
18 (100%)
18 (100%)
17 (95%)
11 (61%)
Medications
β-blockers
Selective serotonin reuptake
inhibitors (SSRI)
Norepinephrine reuptake inhibitors/SSRI
Midodrine
Modafinil
Fludrocortisone
Pyridostigmine
Octreotide
Erythropoietin
Comorbid conditions
Hypermobility
Hypertension
Diabetes Mellitus
Migraine
Precipitating factor
None
Infectious mononucleosis
Heart rate (beats per minute)
Systolic blood pressure (mmHg)
Standing
72.2 ± 10
129 ± 16
121 ± 14
122 ± 16
strated a typical POTS pattern with minimal
change in blood pressure and an increase in
heart rate in an office-based physical examination,
confirming their diagnosis of postural orthostatic
tachycardia (Table II). Each of these patients
was further evaluated by a standard HUTT. The
HUTT confirmed the diagnosis of POTS, but in
addition, continuing the tilt beyond 10 minutes
demonstrated a response consistent with NCS.
Thus, a dual response was noted on a HUTT
with initial POTS followed by neurocardiogenic
decompensation pattern (see Table III and Fig. 1).
Continued tilting beyond 10 minutes resulted in
a sudden decline in heart rate (which in some
patients manifested as an asystole that lasted
anywhere between 10 and 32 seconds, mean of
18 seconds).
The mean time to the NCS pattern of a fall in
blood and heart was 15 minutes with a range of 13–
20 minutes. Thirteen patients demonstrated NCS
without a provocative isoproterenol infusion and
three patients demonstrated NCS response after
isoproterenol infusion.
9 (50%)
8 (45)
11 (61%)
9 (50%)
3 (16%)
4 (22%)
17 (94%)
1 (6%)
4 (22%)
4 (22%)
4 (22)
1 (6%)
9 (50%)
10 (83.3%)
2 (16.6%)
the clinical features, comorbid conditions, and
medications used in these patients.
This group of patients was highly symptomatic with frequent clinical symptoms that were
suggestive of OI. Recurrent presyncope, syncope,
orthostatic palpitations, exercise intolerance, and
fatigue were the dominant symptoms reported.
Each of these patients carried a diagnosis of
POTS initially, but due to the nature of their
symptoms each patient was further evaluated by a
HUTT.
Table III.
Heart Rate and Blood Pressure Response in Patients
with Combined Orthostatic Intolerance on a HUTT. Note
a Dual Response with Initial Pattern Consistent with
POTS (Increase in Heart and Minimal Change in Blood
Pressure); Prolonged Tilting at 20 Minutes Demonstrated
a Typical Neurocardiogenic Pattern with Fall in Heart
Rate Associated with Fall in Blood Pressure
HUTT Response
All the patients reported here had clinical
features and a physical exam consistent with the
diagnosis of POTS. In view of their refractory
symptoms and frequent syncope, they were
referred to our center for further evaluation. A
detailed physical examination was performed in
each of these patients. All of these patients demon-
PACE
Sitting
0 minutes 10 minutes 20 minutes
Heart rate (beats
per minute)
Blood pressure
(mmHg)
2010
73 ± 10
123 ± 15
43 ± 15
126 ± 15
118 ± 14
75 ± 12
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KANJWAL, ET AL.
derstood as a physiological state most commonly
due to inability of the peripheral vasculature
to maintain adequate resistance in the face of
orthostatic stress, allowing for excessive pooling of
blood in the more dependent areas of the body.10,11
The resultant functional decline in circulatory
volume elicited a compensatory increase in
heart rate and myocardial contractility. While
compensatory in mild cases, this mechanism is
unable to fully compensate in more severe cases,
resulting in a reduction in effective circulation
and varying degrees of cerebral hypoperfusion.
Later investigations revealed that POTS is not a
single condition, but rather a heterogeneous group
of disorders resulting in similar physiological
state.9–13
Recent research has shown that this syndrome
may have multiple etiologies and we now know
that POTS can have multiple variants such
as partial dysautonomia,9 centrally mediated
hyperadrenergic stimulation,12,13 norepinephrine
transporter dysfunction,14 and an autoimmune antibody against acetylycholinesterase receptors,15
POTS associated with deconditioning,15 and
hypovolumia.16 In a recently published study, it
was reported that POTS may be a manifestation of
autonomic cardiac neuropathy.17
More recently, interest has grown in the assessment of parasympathetic function in patients
suffering from POTS. Raj reported a group of POTS
patients in whom vagal function was preserved
as assessed by normal sinus arrhythmia ratio on
deep breathing.18 Alshekhlee et al. describe a
series of four POTS patients who had a surge
of parasympathetic activity resulting in marked
cardioinhibition and vasodepression.19 They postulated that either a compensatory parasympathetic surge or a central aberration altering both
sympathetic as well as parasympathetic output
in a balanced fashion may account for increased
parasympathetic activity in this group of patients.
We postulate that an initial compensatory
increase in sympathetic outflow that increases the
inotropy as well as chronotropy of the heart may
fatigue or norepinephrine stores may become exhausted, resulting in a state of relative sympathetic
withdrawal causing a state of bradycardia and
hypotension in this group of patients. Assessing
both sympathetic as well parasympathetic nervous
system function at various stages of the HUTT
may answer many of the questions, which our
report could not address. Ojha et al. have reported
that as many as 38% of patients suffering from
POTS experience syncope during HUTT, and they
suggest that the low-pressure baroreceptors that
have been implicated as contributing to some
forms of POTS may confer upon these patients an
increased risk of syncope.20 In a recent study from
Figure 1. Line diagram demonstrating a dual response
with initial pattern consistent with POTS (increase in
heart and minimal change in blood pressure); prolonged
tilting at 20 minutes demonstrated a typical neurocardiogenic pattern with fall in heart rate associated with
fall in blood pressure.
Response to Medications
All of these patients failed first-line medications. Second-line medications including pyridostigmine was tried in 17 of 18 patients. Of
these 17 patients, improvement in symptoms
of OI was observed in five patients only. None of
these patients had complete elimination of their
syncope. However, a subjective improvement in
the severity and frequency of symptoms of OI
intolerance was reported by five (30%) of the
patients treated with pyridostigmine. One patient
is being treated with octreotide and another four
with erythropoietin, as pyridostigmine failed to
improve heart rate and blood pressure in these
patients.
Pacemaker Implantation
Nine patients were further evaluated by
implantable loop recorder (ILR). Five patients
demonstrated prolonged periods of complete heart
block and asystole on the tracings that were
downloaded following episodes of abrupt onset
of convulsive syncope.
Each of these five patients received dualchamber closed loop cardiac pacemaker with nearcomplete elimination of their episodic loss of
consciousness.
Discussion
The exact pathophysiology of postural tachycardia syndrome remains elusive. Our understanding of the disorder now called POTS has
substantially increased in the last two decades.
The early descriptions of the disorder focused on a
group of patients who had been previously healthy
until a sudden febrile illness (presumably viral)
brought on an abrupt onset of symptoms.9 Later
investigations revealed that POTS is better un-
4
2010
PACE
COEXISTING POTS AND NCS
Fu et al.,21 it was observed that patients with POTS
have a smaller heart in comparison to the controls.
Also they observed that the autonomic function
was intact in their group of patients. In this
report, exercise training improved or even cured
symptoms of POTS. With continued research in
the area of OI, we hope to learn more about
the pathophysiology of the POTS and its related
syndromes.
There were some interesting observations
from our study. Syncope (which, as mentioned
previously, occurs in 10%–38% of historical
controls of POTS patients in general) occurred
in all patients in this group. This observation
could be explained by a late-phase surge in
parasympathetic tone or sympathetic withdrawal
leading to both cardio inhibition as well as
vasodepression. Almost all patients in this study
had difficulty treating OI with each patient failing
first- and second-line medications. Response to
third-line medication, including Pyridostigmine,
was also modest. Recently, Ivarbidine, a selective
inhibitor of a cardiac pacemaker current inhibitor,
has been reported to be effective in patients
with inappropriate sinus tachycardia,22 tachycardia with POTS,23 and tachycardia associated
with autonomic dysfunction.24 In one report,23
Ivarbidine was reported to improve symptoms of
POTS in a patient who had failed multiple other
medications. The patient described in the report
had history of intermittent bradycardia and heart
block for which he had received a pacemaker.
Since these results were recently published, none
of our patients had received Ivarbidine so far. But
Ivarbidine therapy may be beneficial in patients
suffering from POTS. In the future, we expect more
studies will be published on the use of Ivarbidine
in postural tachycardia that will define the role of
this therapy in POTS patients a better way.
In our study, the patients who were found to
have prolonged episodes of asystole or complete
heart block on ILR subsequently benefited from
dual-chamber pacemaker placement. Thus, POTS
patients who present with unusually frequent and
severe episodes of syncope should be considered
for evaluation by an ILR to assess whether baradycardia and/or asystole occurs during clinical
events.
Limitations
There were several important limitations in
the current study. The study was retrospective
and included small number of patients. None
of the patients underwent additional autonomic
function assessment besides HUTT. Response
to therapy was subjective and not objectively
assessed by a formal questionnaire or a response
to a repeat HUTT.
Conclusion
NCS may coexist with POTS in a subgroup of
patients suffering from OI. This group of patients
with mixed-form OI may be difficult to treat
and may have syncope as a dominant symptom.
Also, POTS patients presenting with unusually
frequent and severe episodes of syncope may
benefit from further evaluation by ILR, as some
of these patients, having NCS as well, may be
candidates for cardiac pacing.
References
10. Rowe PC, Barron DF, Calkins H, Maumenee IH, Tong PY,
Geraghty MT. Orthostatic intolerance and chronic fatigue syndrome
associated with Ehlers-Danlos syndrome. J Pediatr 1999; 135:494–
499.
11. Gazit Y, Nahir M, Grahame R, Jacob G. Dysautonomia in
the joint hypermobility syndrome. Am J Med 2003; 115:33–
40.
12. Jordan J, Shannon JR, Diedrich A, Black BK, Robertson D: Increased
sympathetic activation in idiopathic orthostatic intolerance: Role
of systemic adrenoreceptor sensitivity. Hypertension 2002; 39:173–
178.
13. Shibao C, Arzubiaga C, Roberts LJ, Raj S, Black B, Harris P, Biaggioni
I. Hyperadrenergic postural tachycardia syndrome in mast cell
activation disorders. Hypertension 2005; 45:385–390.
14. Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon
VA. Autoantibodies to ganglionic acetylcholine receptors in
autoimmune autonomic neuropathies. N Engl J Med 2000; 343:847–
855.
15. Levine BD, Zuckerman JH, Pawelczyk JA. Cardiac atrophy after
bed-rest deconditioning: A nonneural mechanism for orthostatic
intolerance. Circulation 1997; 96:517–525.
16. Raj SR, Robertson D. Blood volume perturbations in the postural
tachycardia syndrome. Am J Med Sci 2007; 334:57–60.
17. Haensch CA, Lerch H, Schlemmer H, Jigalin A, Isenmann S. Cardiac
neurotransmission imaging with 123I-meta-iodobenzylguanidine
in postural tachycardia syndrome. J Neurol Neurosurg Psychiatry
2010; 81:339–343.
1. Grubb BP. Dysautonomic (orthostatic) syncope. In: Grubb BP,
Olshansky B (eds.): Syncope: Mechanisms and Management.
Malden, MA, Blackwell Publishing, 2005, pp. 72–91.
2. Grubb BP. Neurocardiogenic syncope. In: Grubb BP, Olshansky
B (eds.): Syncope: Mechanisms and Management. Malden, MA,
Blackwell Publishing, 2005, pp. 47–71.
3. Grubb BP. Neurocardiogenic syncope and related disorders of
orthostatic intolerance. Circulation 2005; 111:2997–3006.
4. Grubb BP. Postural orthostatic Tachycardia. Circulation 2008;
117:2814–2817.
5. Kanjwal Y, Kosinski D, Grubb BP. The postural orthostatic
tachycardia syndrome: Definitions, diagnosis, and management.
Pacing Clin Electrophysiol 2003; 26:1747–1757. Review.
6. Grubb BP, Kosinski DJ, Kanjwal Y. Orthostatic hypotension: Causes,
classification, and treatment. Pacing Clin Electrophysiol 2003; 26(4
Pt1):892–901. Review. PubMed PMID: 12715851.
7. Kanjwal Y, Kosinski D, Grubb BP. The postural orthostatic
tachycardia syndrome: Definitions, diagnosis, and management.
Pacing Clin Electrophysiol 2003; 26:1747–1757. Review. PubMed
PMID: 12877710.
8. Grubb BP, Kanjwal MY, Kosinski DJ. Review: The postural orthostatic tachycardia syndrome: Current concepts in pathophysiology
diagnosis and management. J Interv Card Electrophysiol 2001; 5:9–
16.
9. Jacob G, Costa F, Shannon JR, Robertson RM, Wathen M, Stein M,
Biaggioni I, et al. The neuropathic postural tachycardia syndrome.
N Engl J Med 2000; 343:1008–1014.
PACE
2010
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KANJWAL, ET AL.
22. Calo` L, Rebecchi M, Sette A, Martino A, de Ruvo E, Sciarra L,
De Luca L, et al. Efficacy of ivabradine administration in patients
affected by inappropriate sinus tachycardia. Heart Rhythm 2010;
7:1318–1323.
23. Khan S, Hamid S, Rinaldi C. Treatment of inappropriate
sinus tachycardia with ivabradine in a patient with postural orthostatic tachycardia syndrome and a dual chamber pacemaker. Pacing Clin Electrophysiol 2009; 32:131–
133.
24. Aliyev F, Celiker C, Turko˘
glu C, Uzunhasan I. Successful use of
¨
ivabradine in a case of exaggerated autonomic dysfunction. Turk
Kardiyol Dern Ars 2010; 38:285–289.
18. Raj SR. The Postural Tachycardia Syndrome (POTS): Pathophysiology, diagnosis and management. Indian Pacing Electrophysiol J
2006; 6:84–99.
19. Alshekhlee A, Guerch M, Ridha F, Mcneeley K, Chelimsky TC.
Postural tachycardia syndrome with asystole on head-up tilt. Clin
Auton Res 2008; 18:36–39.
20. Ojha, A, McNeeley K, Heller E, Alshekhlee A, Chelimsky G,
Chelimsky T. Orthostatic syndromes differ in syncope frequency.
Am J Med 2010; 123:245–249.
21. Fu Q, Vangundy TB, Galbreath MM, Shibata S, Jain M, Hastings
JL, Bhella PS, et al. Cardiac origins of the postural orthostatic
tachycardia syndrome. J Am Coll Cardiol 2010; 55:2858–2868.
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